Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

INTRODUCTION: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. METHODS: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. RESULTS: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. CONCLUSIONS: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.

Dynamics of creatinine estimated glomerular filtration rate using one or more antiretrovirals that inhibit creatinine tubular secretion.

BACKGROUND: Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. METHODS: Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient's characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multivariate analyses. RESULTS: The analysis included 725 patients. At 48 weeks, the combination of two or more IPTCrS (darunavir/cobicistat with rilpivirine and/or dolutegravir) was associated with higher decreases in Cr-eGFR [adjusted median difference (±SD) -3.5 ± 1.6 (95% CI -6.6 to -0.3), P = 0.047], and a decrease up to or higher than 15 mL/min/1.73 m2 was more frequent [adjusted OR 3.233 (95% CI 1.343-7.782), P = 0.009], with respect to darunavir/cobicistat alone. The Cr-eGFR changes between darunavir/cobicistat and darunavir/cobicistat with rilpivirine and/or dolutegravir showed more significant decreases in patients taking two or more IPTCrS at 12, 24 and 48 weeks. (ClinicalTrials.gov: NCT03042390). CONCLUSIONS: Concomitant use of darunavir/cobicistat plus IPTCrS dolutegravir, rilpivirine, or both produced an additive effect in the expected Cr-eGFR decrease.

Dual therapy based on a ritonavir-boosted protease inhibitor as a novel salvage strategy for HIV-1-infected patients on a failing antiretroviral regimen.

OBJECTIVES: To assess the efficacy and safety of dual-antiretroviral therapy containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced patients failing a current antiretroviral regimen. METHODS: Retrospective analysis of 60 consecutive HIV-1-infected patients who started a dual-antiretroviral rescue regimen containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV RNA >50 copies/mL at treatment week 24 or later. The percentage of patients remaining free of therapeutic failure was estimated using the Kaplan-Meier method, by intent-to-treat analysis (missing, changes and virological failure = therapeutic failure). RESULTS: Median baseline characteristics of patients were: 13 years on antiretroviral therapy (four prior highly active antiretroviral therapy regimens and eight different drugs), 380 CD4 cells/mm(3) and HIV RNA 3.04 log(10) copies/mL. All patients had resistance mutations to at least two drug classes, although only 9.3% had specific mutations to darunavir. A darunavir-based regimen was started in 47 (78.4%) patients, combined with etravirine (26.7%), tenofovir (26.7%) or raltegravir (25%). Three (5%) patients discontinued treatment due to side effects. At the end of follow-up, 86.7% of patients remained free of therapeutic failure; the percentages of patients with no therapeutic failure at treatment weeks 24, 48 and 96 were 96.6% (95% CI, 91.9-101.3); 90.1% (95% CI, 81.9-98.3) and 79.8% (95% CI, 66.1-93.5), respectively. CONCLUSIONS: Our results suggest that a dual-therapy rescue regimen including a PI/r is convenient, well tolerated and potent enough to achieve persistent viral suppression in selected pre-treated patients with low viral load and few PI resistance mutations.

Simplification to dual antiretroviral therapy including a ritonavir-boosted protease inhibitor in treatment-experienced HIV-1-infected patients.

OBJECTIVES: To assess the effectiveness of simplification to a dual antiretroviral regimen containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced HIV-1-infected patients. METHODS: Retrospective analysis of 131 HIV-1-infected patients on suppressive antiretroviral treatment (HIV-RNA <50 copies/mL) who switched to a maintenance dual antiretroviral regimen, containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV-RNA >50 copies/mL. The percentage of patients remaining free of therapeutic failure was estimated using the time-to-loss-of-therapeutic-response algorithm, by intent-to-treat analysis. RESULTS: Median baseline characteristics of the patients were 14 years on antiretroviral therapy, five prior HAART regimens and 10 different drugs, 24 months on a suppressive regimen and 522 CD4+ cells/mL. Reasons for simplification to dual therapy were nucleoside reverse transcriptase inhibitor-related toxicity (46.6%), removal of lamivudine/emtricitabine due to resistance (16.8%), simplification from regimens containing a dual PI, enfuvirtide or tipranavir (20.6%) and simplification from other complex regimens (16.0%). Darunavir (58.0%), lopinavir (16.8%) or atazanavir (13.0%) were the preferred PIs, used in combination with tenofovir (50.4%), raltegravir (22.1%) or etravirine (12.2%). At the end of follow-up (median 14 months), 90.1% of patients remained free of therapeutic failure; corresponding data at treatment weeks 24, 48 and 96 were 93.6% (95% CI, 89.3-97.9), 90.9% (95% CI, 84.9-95.9) and 87.4% (95% CI, 80.7-94.1), respectively. Two (1.5%) patients had virological failure and 11 (8.4%) discontinued treatment due to side effects or were lost to follow-up. CONCLUSIONS: Simplification to a dual-therapy regimen including a PI/r might be useful to enhance convenience and/or diminish toxicity in selected treatment-experienced patients.

Identification of recent HIV-1 infection among newly diagnosed cases in Catalonia, Spain (2006-08).

BACKGROUND: Quantification and description of patients recently infected by HIV can provide an accurate estimate of the dynamics of HIV transmission. Between 2006 and 2008 in Catalonia, we estimated the prevalence of recent HIV infection among newly diagnosed cases, described the epidemiological characteristics of the infection according to whether it was recent, long-standing or advanced, and identified factors associated with recent infection. METHODS: A Test for Recent Infection (TRI) was performed in serum samples from patients newly diagnosed with HIV. Two different TRI were used: the Vironostika-LS assay (January 2006-May 2007) and the BED-CEIA CEIA (June 2007 onwards). Samples were obtained within the first 6 months of diagnosis. Patients whose samples tested positive in the TRI were considered recently infected. RESULTS: Of 1125 newly diagnosed patients, 79.9% were men (median age, 35.4 years), 38.7% were born outside Spain, 48.9% were men who have sex with men (MSM) and 10.6% presented other sexually transmitted infections. The overall percentage of recent infection was 23.0%, which increased significantly, from 18.1% in 2006 to 26.2% in 2008. This percentage was higher for patients from South America (27.6%). Factors associated with recent infection were acquiring infection through sexual contact between MSM [odds ratio (OR) 2.0; 95% confidence interval (95% CI) 1.1-3.9], compared with acquiring infection through heterosexual relations and being under 30 years of age (OR 5.9; 95% CI 1.9-17.4), compared with being over 50 years of age. CONCLUSION: The highest percentage of recent infection was identified in MSM, suggesting either a higher incidence or a greater frequency of HIV testing. Information regarding testing patterns is necessary to correctly interpret data from recently infected individuals. Systems to monitor the HIV epidemic should include both parameters.

Dyslipidaemia in HIV-infected women on antiretroviral therapy. Analysis of 922 patients from the Spanish VACH cohort.

BACKGROUND: Information concerning lipid disturbances in HIV-infected women on antiretroviral therapy (ART) is scarce. The objective of the study is to describe the lipid profile in a large cohort of HIV-infected women on contemporary ART and analyse differences between regimes and patient's characteristics. METHODS: Observational, multicentre, cross-sectional study from the Spanish VACH Cohort. 922 women on stable ART without lipid-lowering treatment were included. RESULTS: Median age was 42 years, median CD4 lymphocyte count was 544 cells/mm3, and 85.6% presented undetectable HIV-1 viral load. Median total cholesterol (TC) was 189 mg/dL (interquartile range, IQR, 165-221), HDL cholesterol 53 mg/dL (IQR, 44-64), LDL cholesterol 108 mg/dL (IQR, 86-134), and triglycerides 116 mg/dL (IQR, 85-163). Mean accumulated time on ART was 116 months; 47.4% were on NNRTI-based regimes, 44.7% on PI, and 6.7% on only-NRTI therapy. 43.8% were also hepatitis C (HCV) coinfected. Patients on PI treatment presented higher TC/HDL ratio than those on NNRTI (p < 0.001). Significantly higher HDL values were observed in NNRTI-treated patients. HCV-coinfected patients presented lower TC/HDL ratio than the non HCV-coinfected. In multivariate analysis, factors independently associated with TC/HDL ratio were age, triglyceride levels and HCV co-infection. PI treatment presented a non-significant association with higher TC/HDL ratio. CONCLUSIONS: In HIV-infected women, the NNRTI-based ART is associated with a better lipid profile than the PI-based. Factors unrelated to ART selection may also exert an independent, significant influence on lipids; in particular, age, and triglyceride levels are associated with an increased TC/HDL ratio while HCV co-infection is associated with a reduced TC/HDL ratio.

Epidemiological characteristics and predictors of late presentation of HIV infection in Barcelona (Spain) during the period 2001-2009.

BACKGROUND: Early diagnosis of HIV infection can prevent morbidity and mortality as well as reduce HIV transmission. The aim of the present study was to assess prevalence, describe trends and identify factors associated with late presentation of HIV infection in Barcelona (Spain) during the period 2001-09. METHODS: Demographic and epidemiological characteristics of cases reported to the Barcelona HIV surveillance system were analysed. Late presentation was defined for individuals with a CD4 count below 350 cells/ml upon HIV diagnosis or diagnosis of AIDS within 3 months of HIV diagnosis. Multivariate logistic regression were used to identify predictors of late presentation. RESULTS: Of the 2,938 newly diagnosed HIV-infected individuals, 2,507 (85,3%) had either a CD4 cell count or an AIDS diagnosis available. A total of 1,139 (55.6%) of the 2,507 studied cases over these nine years were late presenters varying from 48% among men who have sex with men to 70% among heterosexual men. The proportion of late presentation was 62.7% in 2001-2003, 51.9% in 2004-2005, 52.6% in 2006-2007 and 52.1% in 2008-2009. A decrease over time only was observed between 2001-2003 and 2004-2005 (p = 0.001) but remained constant thereafter (p = 0.9). Independent risk factors for late presentation were older age at diagnosis (p < 0.0001), use of injected drugs by men (p < 0.0001), being a heterosexual men (p < 0.0001), and being born in South America (p < 0.0001) or sub-Saharan Africa (p = 0.002). CONCLUSION: Late presentation of HIV is still too frequent in all transmission groups in spite of a strong commitment with HIV prevention in our city. It is necessary to develop interventions that increase HIV testing and facilitate earlier entry into HIV care.

Prevalence of transmitted antiretroviral resistance and distribution of HIV-1 subtypes among patients with recent infection in Catalonia (Spain) between 2003 and 2005.

OBJECTIVES: The objectives of this study were to assess the prevalence of transmitted HIV-1 drug resistances (TDR) and HIV-1 subtypes in recently infected patients in Catalonia between 2003 and 2005 and to describe the characteristics of these patients according to the presence or absence of TDR and HIV-1 subtype. METHODS: After application of the Serological Testing Algorithm for Recent HIV Seroconversion (STARHS), residual aliquots of serum samples from recently infected antiretroviral-naïve individuals were genotyped. FASTA sequences were analyzed using the HIVDB Program. The World Health Organization 2009 List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistant HIV Strains was used to estimate the prevalence of TDR. RESULTS: Of 182 recently infected patients, 14 (7.7%) presented TDR. Seven (3.8%) had genotypic evidence of TDR against non-nucleoside reverse transcriptase inhibitors, 6 (3.3%) against nucleoside reverse transcriptase inhibitors, 3 (1.6%) against protease inhibitors (PIs), and only 2 individuals (1.1%) presented TDR against more than one class of drugs. Thirty-five (19.2%) patients were infected with a non-B HIV-1 subtype. CONCLUSION: This is the first study to estimate the prevalence of TDR in recently infected patients in Catalonia. The results are similar to those of studies performed in other Spanish regions. Correct monitoring of these parameters requires systematic epidemiologic surveillance of transmitted resistance.

Efficacy and safety of switching to dolutegravir plus lamivudine versus continuing triple antiretroviral therapy in virologically suppressed adults with HIV at 48 weeks (DOLAM): a randomised non-inferiority trial.

BACKGROUND: Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy. METHODS: DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per µL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435. FINDINGS: Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0·8 percentage points (95% CI -3·3 to 5·2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0·68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group. INTERPRETATION: Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART. FUNDING: Instituto de Salud Carlos III, Red de Investigación en Sida, and ViiV Healthcare.

eGFR-EPI changes among HIV patients who switch from F/TDF to F/TAF while maintaining the same third agent in the Spanish VACH cohort.

Background: Evidence from clinical practice on the effects of switching from emtricitabine/tenofovir disoproxil fumarate (F/TDF) to emtricitabine/tenofovir alafenamide (F/TAF)-based triple-therapy (TT) regimens on renal parameters is limited.Objective: This retrospective analysis evaluated the effects on renal function of switching from F/TDF to F/TAF-based TT regimens with no change in third agent among people living with HIV (PLWH).Methods: Data were from a multicenter Spanish PLWH cohort. Patients with a baseline estimated glomerular filtration rate (eGFR-EPI) measurement, ≥1 follow-up measurement, ≥30 days treatment with F/TAF, and who switched from F/TDF to F/TAF with no change in third agent were included. Multivariate mixed linear models were used to evaluate change from baseline over time in eGFR-EPI. eGFR-EPI changes before and after switch were analyzed in a matched patient subgroup.Results: Overall, 340 patients were included. Mean (95% CI) eGFR-EPI in patients with baseline eGFR-EPI <90 ml/min/1.73m2 (n = 125) was 79.6 (78.0; 81.2) ml/min/1.73m2 at baseline and 81.3 (79.9; 82.7) ml/min/1.73m2 at 12 months after switch. In the patient-matched subgroup (n = 175), median annual eGFR-EPI declined -4.24 ml/min/1.73m2 while on F/TDF and increased +0.93 ml/min/1.73m2 after switch to F/TAF (P < 0.0001). In patients with baseline eGFR-EPI <90 ml/min/1.73m2, median annual eGFR-EPI increased +4.19 mL/min/1.73m2 after switch (P < 0.0001).Conclusion: Switching from F/TDF to F/TAF-based TT regimens while maintaining the same third agent numerically improved eGFR-EPI in PLWH with baseline eGFR-EPI <90 mL/min/1.73m2. eGFR-EPI improved significantly when comparing progression while on F/TDF vs progression after switch, confirming beneficial renal effects of switching to F/TAF in a clinical practice setting.

Long-term efficacy and safety of nevirapine-containing regimens in virologically suppressed patients: a 17-year follow up.

Background: To evaluate long term outcomes in patients maintaining a NVP based regimen for more than 10 years.Materials and methods: Retrospective, multicenter, cohort study including virologically suppressed patients, currently receiving a NVP-based regimen that had been started at least 10 years previously. Demographic, clinical, and analytical variables were recorded.Results: Two hundred and seventy four subjects were included. Median (IQR) follow up was 17.1 (13.8-18.5) years. Dyslipidemia (29.9%), hypertension (11.4%) and diabetes (8%) were the most common reported co-morbidities. After a median of 17 years of follow-up we observed a significant increase in general health markers such as hemoglobin and CD4 cells (all p<0.001) as well as a significant reduction in CD8 and ALT [-111 cells/uL (-346.5-151) p 0.003 and ALT median (IQR) -4.2 (-18.5-4) p<0.001 respectively]. LDL-c and serum triglyceride levels decreased significantly [-0,1 (-1-0.6) p:<0.001 and -0,3 (-1.2-0.4) p:0.002 respectively]. HDL-c increased significantly 0.3 (00.5-0.6). Median (IQR) time with persistent HIV VL <50 copies was 16 (13-18) years. During follow up, subjects presented with median (IQR) 1 (0-2) blip (HIV VL >50<1000 copies/ml).Conclusions: Based on the extensive experience as well as a good tolerance and efficacy profile, NVP should be considered for treatment continuation in those patients already receiving this inexpensive generic drug.

Brief Report: Effectiveness of Trichloroacetic Acid vs. Electrocautery Ablation for the Treatment of Anal High-Grade Squamous Intraepithelial Lesion in HIV-Infected Patients.

BACKGROUND: Trichloroacetic acid (TCA) and electrocautery ablation (ECA) are 2 of the main treatment options for anal high-grade squamous intraepithelial lesion (HSIL). Our aim was to compare the efficacy and tolerance of TCA vs. ECA for HSIL. METHODS: Retrospective uncontrolled study of HIV-infected men who have sex with men who had an anal HSIL treated with TCA or ECA. On-treatment effectiveness was evaluated at 6-8 weeks after treatment. A complete response was defined as resolution of HSIL, a partial response as regression to low-grade lesion, and recurrence as biopsy-proven HSIL during follow-up. A propensity-score analysis was used to adjust efficacy to potential confounding. RESULTS: From May 2009 to March 2018, 182 and 56 cases of anal HSIL were treated with ECA and TCA, respectively. Comparing ECA with TCA, a complete response was observed in 33.5% (95% confidence interval: 25.8 to 41.6) vs. 60.7% (50.0 to 74.8) and a partial response in 28.0% (20.3 to 36.0) vs. 23.2% (12.5 to 37.3), respectively (P < 0.001). These differences were maintained in the propensity-score analyses. Side effects were common in both treatment, but tolerance was reported as good in 80.6% (74.2 to 89.2) and 82.6% (73.9 to 93.9) of cases treated with ECA and TCA, respectively, and no serious events were described. Recurrence cumulative incidence for the first 12 months was 14.6% (9.1 to 23.1) for ECA episodes and 27.6% (11.5 to 57.7) for TCA (P = 0.183). CONCLUSIONS: Our study showed a higher efficacy of TCA than ECA with similar rates of side effects. In our opinion, considering the benefits of TCA, it should be considered as a first-line therapy for most anal HSIL management.

Effectiveness of polysaccharide pneumococcal vaccine in HIV-infected patients: a case-control study.

BACKGROUND: Polysaccharide pneumococcal vaccine (PPV) is recommended among human immunodeficiency virus (HIV)-infected patients, although its effect in reducing the incidence of pneumonia or invasive pneumococcal disease is not well established. Our objective was to determine the effectiveness of 23-valent PPV in HIV-infected adults and the risk factors for pneumococcal pneumonia or invasive pneumococcal disease. METHODS: We performed a retrospective case-control study in 4 Spanish hospitals for the period from January 1995 through December 2005 using the HIV database from each hospital to identify case patients with Streptococcus pneumoniae disease and control subjects without a history of pneumococcal infection. RESULTS: A total of 184 case patients and 552 control subjects were identified. The factors associated with pneumococcal disease in bivariate analysis were active injection drug use (odds ratio [OR], 3.33; 95% confidence interval [CI], 2-5.55), alcoholism (OR, 3.03; 95% CI, 1.86-4.91), chronic obstructive pulmonary disease (OR, 2.58; 95% CI, 1.3-5.1), cirrhosis (OR, 6.05; 95% CI, 3.2-11.4), antiretroviral therapy (OR, 0.23; 95% CI, 0.16-0.32), trimethoprim-sulfamethoxazole prophylaxis (OR, 0.66; 95% CI, 0.45-0.97), viral load <5000 copies/mL (OR, 0.38; 95% CI, 0.26-0.54), and previous PPV (OR, 0.39; 95% CI, 0.24-0.65). Risk factors for pneumococcal disease in multivariate analysis were cirrhosis (OR, 5.64; 95% CI, 2.53-12.53), chronic obstructive pulmonary disease (OR, 2.90; 95% CI, 1.21-6.94), and alcoholism (OR, 2.15; 95% CI, 1.11-4.19), whereas protective factors were receipt of antiretroviral therapy (OR, 0.23; 95% CI, 0.14-0.36) and receipt of pneumococcal vaccine (OR, 0.44; 95% CI, 0.22-0.88), even in patients with CD4 lymphocyte counts <200 cells/microL. CONCLUSIONS: Antiretroviral therapy and PPV have a significant, independent protective effect against pneumococcal disease, regardless of CD4 lymphocyte count; thus, all patients with HIV infection should be vaccinated with PPV to prevent pneumococcal disease.

[Efficacy and safety of a reduced-dose of stavudine in HIV-infected patients under immunological and virological stable conditions]. / Impacto de la reducción de dosis de estavudina en su perfil de eficacia/seguridad en pacientes con infección por el virus de la inmunodeficiencia humana inmunológica y virológicamente estables.

BACKGROUND AND OBJECTIVE: Stavudine (d4T) has shown a favourable short and long-term tolerability profile. Nevertheless, its usage is currently decreasing due to some safety concerns. We aimed to evaluate the efficacy and safety of d4T low-dose-based regimens. PATIENTS AND METHOD: This was a multicenter and retrospective review chart of patients receiving standard doses of d4T for > or = 6 months (weight > 60 kg: 40 mg/12 h; weight < 60 kg: 30 mg/12 h) and having undetectable viral load for at least 3 months before the d4T dose reduction (weight > 60 kg: 30 mg/12 h; weight < 60 kg: 20 mg/12 h). Immunological and viral parametres, lipid profile and side effects were determined. RESULTS: A total of 982 patients were included. The main reason for reducing the dose was prevention of toxicity (76%). After 6 months of follow-up, 97% and 84% patients had less than 400 and 50 cp/ml, respectively, and the CD4 cell count increased by 38 cel/ml. Lipids, lipodystrophy and peripheral polineuropathy improved but there was no statistical significance. CONCLUSIONS: A d4T dose reduction in an immuno-virologically stable population does not affect treatment efficacy. Longer follow-ups are required to confirm improvements in the safety profile.

The role of oncogenic human papillomavirus determination for diagnosis of high-grade anal intraepithelial neoplasia in HIV-infected MSM.

OBJECTIVE: To assess the oncogenic human papillomavirus (HPV) determination and the cotesting HPV and anal cytology value to detect high-grade anal intraepithelial neoplasia (HGAIN) in a cohort of HIV-MSM. DESIGN AND METHODS: Prospective study of HIV-infected MSM who underwent screening for anal dysplasia. Screening program includes anal cytology, HPV testing, and high-resolution anoscopy (HRA) at each visit. Histological samples were obtained if suspicious lesions were revealed by HRA. Sensitivity and specificity of the different tests were calculated by using histological results of HRA-guided biopsy as the reference test for HGAIN diagnosis. RESULTS: From May 2009 to August 2016, 692 HIV-infected MSM underwent 1827 anal cytologies, 1841 HRA examinations, and 1607 HPV testing. At first screening visit, anal cytology results were abnormal in 418 (60.4%) of 692 patients, and oncogenic HPV genotypes were found in 482 (79.5%) of 606 patients. Anal cytology showed a sensitivity of 89.2% [95% confidence interval (CI); 80.7-94.2] and a specificity of 44.2% (95% CI; 40.2-48.2) to detect HGAIN. Oncogenic HPV testing had 90.4% sensitivity (95% CI; 82-86.8) and 24.4% specificity (95% CI; 20.8-28.3). Cotesting showed a 97.4% sensitivity (95% CI; 91-99.3) and 14% specificity (95% CI; 11.2-17.3). In patients with atypical squamous cells of uncertain significance on cytology, oncogenic HPV testing had 91.3% sensitivity and 28.3% specificity to detect HGAIN. CONCLUSION: Abnormal cytology and oncogenic HPV determination showed similar sensitivity for detecting HGAIN. The two tests used together improved the sensitivity but with lowered specificity. In our opinion, HPV testing does not improve HGAIN detection and should not replace anal cytology as a standard screening test for HIV-infected MSM.

Long-term safety and efficacy of nevirapine-based approaches in HIV type 1-infected patients.

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31-51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of <50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85-7.78, p < 0.001), first-line treatment (OR: 3.02, 95% CI: 1.52-6.00, p = 0.002), and baseline CD4 cells >400 cells/microl (OR: 2.34, 95% CI: 1.22-4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.

Performance of six different ritonavir-boosted protease inhibitor-based regimens in heavily antiretroviral-experienced HIV-infected patients.

BACKGROUND: Regimens based on ritonavir-boosted protease inhibitors (PI/r) are often used as rescue interventions. It is unclear whether significant differences exist between distinct PI/r. METHOD: All HIV+ patients who had experienced PI failure at two HIV clinics and were rescued with a regimen based on saquinavir (SQV)/r 1000/100 mg bid, indinavir (IDV)/r 800/100 mg bid, lopinavir (LPV)/r 400/100 mg bid, amprenavir (APV)/r 600/100 mg bid, atazanavir (ATV)/r 300/100 mg qd, or tipranavir (TPV)/r 500/200 mg bid were retrospectively examined. A significant virological response (VR) was defined as >1 log reduction in plasma HIV-RNA or to <50 copies/mL at week 24. RESULTS: A total of 389 patients were included in the analysis: 139 on SQV/r, 35 on IDV/r, 129 on LPV/r, 35 on APV/r, 29 on ATV/r, and 22 on TPV/r. No significant differences in HIV-RNA and CD4 counts at baseline were recognized between groups. In a multivariate analysis, only the total number of protease resistance mutations was associated with a lower VR (odds ratio [OR] = 0.77, 95% CI 0.68-0.87, p < .001). The presence of <5 or > or =5 protease resistance mutations at baseline was the best threshold to discriminate the achievement of VR in any treatment group. In an intent-to-treat analysis, for individuals with 5 protease resistance mutations, the rates of VR were 64% with TPV/r, 47% with LPV/r, 46% with SQV/r, 33% with ATV/r, 25% with IDV/r, and 16% with APV/r. Adverse events leading to treatment withdrawal occurred more frequently using IDV/r (22.8%) than others (p = .03). CONCLUSION: The rate of VR in salvage therapy using PI/r-based regimens is relatively high in PI-experienced patients. The efficacy is greatly influenced by the number of baseline protease resistance mutations; 5 mutations is the best threshold to predict the chances of VR to any PI/r-based regimen.

Genotypic and phenotypic resistance patterns at virological failure in a simplification trial with nevirapine, efavirenz or abacavir.

BACKGROUND: The NEFA Study was a randomized study comparing nevirapine (NVP), efavirenz (EFV) or abacavir (ABC) as substitutes for protease inhibitors in a large group of HIV-1-infected patients successfully treated with antiretroviral regimens containing protease inhibitors. OBJECTIVE: To evaluate genotype and phenotype resistance patterns among patients who have experienced virological failure under one of the three study arms. METHODS: Patients with virological failure, defined as two consecutive determinations of HIV-1 RNA > 200 copies/ml, were analysed for phenotypic susceptibility and HIV-1 mutations. RESULTS: Of the 460 patients included in the study, 51 (11%) experienced virological failure after 24 months of follow-up while on assigned study medication. A higher proportion of patients in the ABC [25 (17%)] than in the NVP [14 (9%)] or EFV [12 (8%)] arms selected resistance to the study drug (P = 0.04). Moreover, a much higher number of resistance mutations to one or more of the backbone nucleoside reverse transcriptase inhibitor drugs contained in the failing regimen were observed in the ABC than in the EFV or NVP arms. In general, there was a good concordance among genotype and phenotype resistance testing, except for ABC, stavudine and didanosine, where phenotypic resistance testing added valuable information (fold change in the median inhibitory concentration). CONCLUSIONS: Cross-resistance involving nucleoside reverse transcriptase inhibitor drugs might explain the higher risk of virological failure in patients switched to ABC-containing antiretroviral therapy. Phenotypic resistance testing may be helpful in interpreting unclear genotypic results.

Therapeutic drug monitoring and the inhibitory quotient of antiretroviral drugs: can they be applied to the current situation?

Therapeutic drug monitoring is attracting growing interest as a means of increasing the effectiveness of antiretroviral therapy and of decreasing its toxicity, although data supporting this strategy are still scarce. Currently, nucleoside analog reverse-transcriptase inhibitors (NARTI) are not candidates because their effect depends on their active intracellular form and not on plasma concentration. Protease inhibitors (PI) and non-nucleoside analogue reverse-transcriptase inhibitors (NNARTI) meet the criteria for therapeutic drug monitoring. The main limitations are that the parameters to be monitored in order to measure exposure to the drug and the effective concentration of the drug have not been well defined. The few studies performed in treatment-naive patients have demonstrated that monitoring improves therapeutic efficacy. This strategy will be particularly useful when the risk of subtherapeutic or toxic concentrations is especially high (pharmacokinetic interactions, intestinal malabsorption, adverse effects, virological failure without obvious cause, pregnancy, children). Although it remains to be standardized, the inhibitory quotient integrates pharmacological and virological parameters and is useful in patients with prior virological failure. Any therapeutic drug monitoring program should be accompanied by measures to monitor and improve treatment adherence. There are good reasons to believe that therapeutic drug monitoring can be useful to improve treatment in specific circumstances. However, before its widespread use as a routine method can be recommended, the parameters to be used should be standardized and studies with appropriate methodology should be performed to define the role of therapeutic drug monitoring in distinct clinical situations.